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Buccal morphine—a new route for analgesia?
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PHARMACOLOGY Thiorphan and analogs: lack of correlation between potency to inhibit ‘enkephalinase A’ in vitro and analgesic potency in vivo. - L.G. Mendelsohn, B.G. Johnson, W.L. Scott and R.C.A. Frederickson, J. Pharmacol. exp. Ther., 234 (1985) 386-390. ‘Enkephalmase A’ which cleaves between the Gly3-Phe4 bond of enkephalins, has been reported to be an important enzyme in the regulation of brain enkephalin levels. It is present in regions of the brain that have high levels of opioid receptors and it is thought to play a role in the inactivation of opioid peptides at the synapse. Inhibitors of enkephalinase A are analgesic when administered alone and enhance analgesia produced by enkephalin analogs. Thus, thiorphan, the most studied enkephalinase inhibitor, significantly reduces the responsiveness of mice in the hot-plate jump test in a naloxone-sensitive way. The specificity of enkephalinase has recently been challenged. For this reason the potencies of the R and S isomers of thiorphan and rigid analogs of thiorpan to produce analgesia in a mouse hot-plate assay have been compared with their potencies to inhibit enkephalin degradation by rat brain ‘enkephalinase A.’ The R and S isomers of thiorphan were equipotent as enzyme inhibitors (IC50 approximately lo-’ M) but had significantly different analgesic profiles when injected i.c.v. Rigid analogs of thiorphan were less potent enzyme inhibitors (IC50 values of lo- ‘-lop4 M) b u t produced analgesia and potentiated Tyr-o-Ala-Gly-Phe-Met-enkephalinamide at doses comparable to thiorphan. These observations suggest that inhibitors of enkephalinase A produce analgesia through a pharmacological mechanism which is not directly related to inhibition of enkephalin degradation. The possibility that enkephalinase inhibitors alter the release of neurotransmitters and/or the degradation of other neuropeptides should be taken into consideration. Buccal morphine - a new route for analgesia? - M.D.D. Bell, P. Mishra, B.D. Weldon, G.R. Murray, T.N. Calvey and N.E. Williams, Lancet, i (1985) 71-73. The analgesic effects of buccal and intramuscular morphine were compared in a prospective. double-blind, double-dummy study in 40 patients who experienced pain after elective orthopaedic operations. Each patient simultaneously received a buccal tablet and an intramuscular injection, only one of which contained morphine sulphate (13.3 mg). The buccal tablets were placed between the upper lip and gum above the incisor teeth. The tablets were usually moistened to facilitate their adherence to the mucosa and they slowly dissolved within 6 h. The patients were randomly allocated to two equal groups, so 20 patients received each active preparation. All patients were assessed before and 5, 10 and 30 min and 1, 2, 3. 4, 5, 6 and 8 h after morphine administration. A visual analogue scale was used. Morphine was extracted from the plasma and its concentration was measured by high-performance liquid chromatography. The two preparations produced a similar degree of postoperative analgesia, assessed by the mean reduction in pain score and the pain relief score. Peak plasma
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morphine concentrations were slightly lower after buccal than after intramuscular administration but they declined more slowly, consequently the drug’s bioavailability was 40-50% greater after buccal than after intramuscular administration. Nausea, vomiting, dizziness and drowsiness were experienced by more patients in the intramuscular group than in the buccal group. Buccal administration had advantages over sublingual drug delivery; the presence of the drug in the mouth is more easily tolerated and it does not stimulate salivation. Buccal administration is therefore a safe and effective method of giving morphine. Potentiation of morphine analgesia by the cholecystokinin antagonist proglumide. - L.R. Watkins, I.B. Kinscheck and D.J. Mayer, Brain Res., 327 (1985) 169-180. Systemic and/or intrathecal administration of the sulphated octapeptide form of cholecystokinin (CCK) can markedly attenuate opiate analgesia produced by systemic morphine, intraventricular beta-endorphin, intrathecal morphine, brief front paw footshock and classical conditioning, but not non-opiate analgesia. In this paper the effect of the CCK receptor antagonist proglumide on various forms of morphine analgesia was examined. It was observed that proglumide can potentiate morphine analgesia following systemic, intrathecal or intracerebral administration of each drug in turn. Endogenous CCK systems do not appear to be tonically active since neither systemic, intrathecal nor intracerebral proglumide typically produced measurable analgesia in the absence of morphine. These data suggest that CCK may be released in response to opiate administration and acts to return the organism toward its basal level of pain sensitivity. If such a hypothesis is in fact true, then CCK blockade may be of clinical value in the treatment of pain. Indeed, recent studies using normal human volunteers have shown that proglumide can enhance the analgesic and psycho-active effects of intravenous morphine.
STOMATOLOGY Spatial summation of pre-pain and pain in human teeth. - A.C. Brown, W.J. Beeler, A.C. Kloka and R.W. Fields, Pain, 21 (1985) l-16. This paper studied the relationship between ‘pre-pain’ and pain sensations evoked by stimulating teeth in human subjects. The subjects readily identified these sensations. By exciting two teeth simultaneously, the authors examined whether spatial summation resulted in a change from ‘pre-pain’ to pain sensations. They assumed that selective activation of ‘non-nociceptive’ fibres should result in more intense ‘pre-pain,’ but not pain sensations, if the tooth pulp contains nerve fibres that signal sensations other than pain. They found that spatial summation of pre-pain resulted in pain rather than in more intense pre-pain. These findings favour the conclusion that the tooth pulp encodes information related to only one sensation, pain, and that pre-pain is due to very low rates of discharge of nociceptive endings.
PHARMACOLOGY Thiorphan and analogs: lack of correlation between potency to inhibit ‘enkephalinase A’ in vitro and analgesic potency in vivo. - L.G. Mendelsohn, B.G. Johnson, W.L. Scott and R.C.A. Frederickson, J. Pharmacol. exp. Ther., 234 (1985) 386-390. ‘Enkephalmase A’ which cleaves between the Gly3-Phe4 bond of enkephalins, has been reported to be an important enzyme in the regulation of brain enkephalin levels. It is present in regions of the brain that have high levels of opioid receptors and it is thought to play a role in the inactivation of opioid peptides at the synapse. Inhibitors of enkephalinase A are analgesic when administered alone and enhance analgesia produced by enkephalin analogs. Thus, thiorphan, the most studied enkephalinase inhibitor, significantly reduces the responsiveness of mice in the hot-plate jump test in a naloxone-sensitive way. The specificity of enkephalinase has recently been challenged. For this reason the potencies of the R and S isomers of thiorphan and rigid analogs of thiorpan to produce analgesia in a mouse hot-plate assay have been compared with their potencies to inhibit enkephalin degradation by rat brain ‘enkephalinase A.’ The R and S isomers of thiorphan were equipotent as enzyme inhibitors (IC50 approximately lo-’ M) but had significantly different analgesic profiles when injected i.c.v. Rigid analogs of thiorphan were less potent enzyme inhibitors (IC50 values of lo- ‘-lop4 M) b u t produced analgesia and potentiated Tyr-o-Ala-Gly-Phe-Met-enkephalinamide at doses comparable to thiorphan. These observations suggest that inhibitors of enkephalinase A produce analgesia through a pharmacological mechanism which is not directly related to inhibition of enkephalin degradation. The possibility that enkephalinase inhibitors alter the release of neurotransmitters and/or the degradation of other neuropeptides should be taken into consideration. Buccal morphine - a new route for analgesia? - M.D.D. Bell, P. Mishra, B.D. Weldon, G.R. Murray, T.N. Calvey and N.E. Williams, Lancet, i (1985) 71-73. The analgesic effects of buccal and intramuscular morphine were compared in a prospective. double-blind, double-dummy study in 40 patients who experienced pain after elective orthopaedic operations. Each patient simultaneously received a buccal tablet and an intramuscular injection, only one of which contained morphine sulphate (13.3 mg). The buccal tablets were placed between the upper lip and gum above the incisor teeth. The tablets were usually moistened to facilitate their adherence to the mucosa and they slowly dissolved within 6 h. The patients were randomly allocated to two equal groups, so 20 patients received each active preparation. All patients were assessed before and 5, 10 and 30 min and 1, 2, 3. 4, 5, 6 and 8 h after morphine administration. A visual analogue scale was used. Morphine was extracted from the plasma and its concentration was measured by high-performance liquid chromatography. The two preparations produced a similar degree of postoperative analgesia, assessed by the mean reduction in pain score and the pain relief score. Peak plasma
405
morphine concentrations were slightly lower after buccal than after intramuscular administration but they declined more slowly, consequently the drug’s bioavailability was 40-50% greater after buccal than after intramuscular administration. Nausea, vomiting, dizziness and drowsiness were experienced by more patients in the intramuscular group than in the buccal group. Buccal administration had advantages over sublingual drug delivery; the presence of the drug in the mouth is more easily tolerated and it does not stimulate salivation. Buccal administration is therefore a safe and effective method of giving morphine. Potentiation of morphine analgesia by the cholecystokinin antagonist proglumide. - L.R. Watkins, I.B. Kinscheck and D.J. Mayer, Brain Res., 327 (1985) 169-180. Systemic and/or intrathecal administration of the sulphated octapeptide form of cholecystokinin (CCK) can markedly attenuate opiate analgesia produced by systemic morphine, intraventricular beta-endorphin, intrathecal morphine, brief front paw footshock and classical conditioning, but not non-opiate analgesia. In this paper the effect of the CCK receptor antagonist proglumide on various forms of morphine analgesia was examined. It was observed that proglumide can potentiate morphine analgesia following systemic, intrathecal or intracerebral administration of each drug in turn. Endogenous CCK systems do not appear to be tonically active since neither systemic, intrathecal nor intracerebral proglumide typically produced measurable analgesia in the absence of morphine. These data suggest that CCK may be released in response to opiate administration and acts to return the organism toward its basal level of pain sensitivity. If such a hypothesis is in fact true, then CCK blockade may be of clinical value in the treatment of pain. Indeed, recent studies using normal human volunteers have shown that proglumide can enhance the analgesic and psycho-active effects of intravenous morphine.
STOMATOLOGY Spatial summation of pre-pain and pain in human teeth. - A.C. Brown, W.J. Beeler, A.C. Kloka and R.W. Fields, Pain, 21 (1985) l-16. This paper studied the relationship between ‘pre-pain’ and pain sensations evoked by stimulating teeth in human subjects. The subjects readily identified these sensations. By exciting two teeth simultaneously, the authors examined whether spatial summation resulted in a change from ‘pre-pain’ to pain sensations. They assumed that selective activation of ‘non-nociceptive’ fibres should result in more intense ‘pre-pain,’ but not pain sensations, if the tooth pulp contains nerve fibres that signal sensations other than pain. They found that spatial summation of pre-pain resulted in pain rather than in more intense pre-pain. These findings favour the conclusion that the tooth pulp encodes information related to only one sensation, pain, and that pre-pain is due to very low rates of discharge of nociceptive endings.